Process for the synthesis of IB-MECA

Abstract

The present disclosure provides a method for the synthesis of IB-MECA. More specifically, the present disclosure provides a simple and high yield method for Good Manufacturing Production (GMP) of IB-MECA. The method involves the reaction of 6-halopurine-9-riboside with a diol protecting reagent; oxidation of the primary alcohol in the diol protected 6-halopurine-9-riboside with a diol protecting reagent; oxidation of the primary alcohol in the diol protected 6-halopurine; reaction of the diol protected 6-halopurine with a nucleophile (e.g. methylamine); substitution of the halogen group with iodobenzylamine and removal of the diol protecting group.

The invention claimed is: 
     
       1. A method for synthesizing IB-MECA of formula (I) 
       
         
           
           
               
               
           
         
         the method comprising: 
         reacting 6-halopurine-9-riboside of formula (II) 
       
       
         
           
           
               
               
           
         
         
           wherein X is a halogen selected from the group consisting of Cl, I and Br, 
           with a diol protecting reagent to obtain a reaction mixture; 
           diluting the reaction mixture with water and crystallizing a diol protected 6-halopurine of formula (III) 
         
       
       
         
           
           
               
               
           
         
         
           the diol protecting reagent comprising a straight or branched C 1 -C 6  alkyl group; 
           oxidizing the primary alcohol in the diol protected 6-halopurine of formula (III), the oxidizing comprising adding a catalytic amount of an oxidizing agent comprising at least one of sodium periodate or ruthenium trichloride to obtain a second reaction mixture; 
           filtering the second reaction mixture; 
           diluting the second reaction mixture and crystallizing a respective carboxylic acid derivative of formula (IV) 
         
       
       
         
           
           
               
               
           
         
         
           reacting the carboxylic acid group of the derivative of formula (IV) with SOCl 2  to obtain an acid chloride followed by reaction with methylamine in the presence of diisopropylethylamine (DIPEA) to obtain a methylamide derivative of the diol protected 6-halopurine (III), the methylamide derivative having formula (V) 
         
       
       
         
           
           
               
               
           
         
         
           substituting the halogen group of methylamide derivative (V) with 3-iodobenzylamine, the 3-iodobenzylamine having a level of impurity less than or equal to 0.92%, in the presence of diisopropylethylamine (DIPEA) to form a diol protected IB-MECA of formula (VI) 
         
       
       
         
           
           
               
               
           
         
         
           purifying the diol protected IB-MECA of formula (VI), the purifying comprising adding methanol and recrystallizing the diol protected IB-MECA of formula (VI), 
           repeating the purifying; 
           removing diol protection to obtain the IB-MECA of formula (I) at a purity level of greater than or equal to 99.5% and at a yield level being suitable for large scale production of the IB-MECA. 
         
       
     
     
       2. The method of  claim 1 , wherein the halogen is chloride. 
     
     
       3. The method of  claim 1 , wherein the protecting group is C 3 -C 6  dialkyloxyalkane. 
     
     
       4. The method of  claim 3 , wherein the dialkyloxyalkane is 2,2-dimethoxypropane. 
     
     
       5. The method of  claim 1 , wherein the diol protection is achieved in the presence of a strong acid and a polar organic solvent. 
     
     
       6. The method of  claim 5 , wherein the strong acid is selected from p-TsOH, methane sulfonic acid, benzene sulfonic acid, formic acid, hydrochloric acid, sulfuric acid. 
     
     
       7. The method of  claim 5 , wherein the polar organic solvent is a water-miscible solvent. 
     
     
       8. The method of  claim 7 , wherein the polar organic solvent is acetone. 
     
     
       9. The method of  claim 1 , wherein the oxidizing agent comprises a mixture of ruthenium trichloride (RuCl 3 ) and sodium periodate. 
     
     
       10. The method of  claim 1 , wherein the removal of the diol protecting group is performed in the presence of a strong acid and a polar non-protic solvent. 
     
     
       11. The method of  claim 10 , wherein the strong acid is HCl and the solvent is Tetrahydrofurane (THF). 
     
     
       12. The method according to  claim 1 , wherein the method consists essentially of performing each step therein in chronological order. 
     
     
       13. A method for synthesizing IB-MECA of formula (I) 
       
         
           
           
               
               
           
         
         the method comprising: 
         reacting 6-halopurine-9-riboside of formula (II) 
       
       
         
           
           
               
               
           
         
         wherein X is a halogen selected from Cl, I or Br, 
         with a diol protecting reagent to obtain a diol protected 6-halopurine of formula (III) 
       
       
         
           
           
               
               
           
         
         wherein the diol protecting reagent comprises a straight or branched C 1 -C 6  alkyl group; 
         oxidizing the primary alcohol in the diol protected 6-halopurine of formula (III) by addition of a catalytic amount of an oxidizing agent comprising at least one or both of sodium periodate and ruthenium trichloride to obtain a respective carboxylic acid derivative of formula (IV) 
       
       
         
           
           
               
               
           
         
         and recrystallizing the acid derivative; 
         reacting the carboxylic acid group of the derivative of formula (IV) with a halogenating agent selected from the group consisting of SOCl 2  and PCl 5  to obtain an acid chloride followed by reaction with methylamine in the presence of diisopropylethylamine (DIPEA) to obtain a methylamide derivative of the diol protected 6-halopurine (III), the methylamide derivative having formula (V) 
       
       
         
           
           
               
               
           
         
         
           substituting the halogen group of methylamide derivative (V) with 3-iodobenzylamine having a level of impurities below 0.92%, in the presence of diisopropylethylamine (DIPEA) to form a diol protected IB-MECA of formula (VI) 
         
       
       
         
           
           
               
               
           
         
         and recrystallizing the diol protected IB-MECA of formula (VI) in methanol; 
         removing diol protection to obtain the IB-MECA of formula (I) at a purity level over 99.5% and yield level being suitable for large scale production of the IB-MECA.